Mitochondria may be the spark that ignites Parkinson’s disease

For a long time, scientists have debated a simple question about Parkinson’s disease: do the cell’s tiny energy factories fail first and spark the disorder, or do they crumble only after brain cells have already begun to die?

The answer is important because it can help experts determine where to aim new treatments.

Parkinson’s is the second most common neurodegenerative disorder. It affects more than one million people in the U.S., and most cases are diagnosed after the age of 60.

Over time, the brain loses its ability to produce the chemical messenger dopamine, which helps control movement. This loss leads to symptoms such as tremor, stiffness, and problems with walking.

Energy factories inside of cells

Inside nearly every cell are mitochondria. They turn nutrients into usable energy so cells can do their jobs. A group at the Gladstone Institutes set out to investigate what happens when these mitochondria malfunction in Parkinson’s.

The researchers focused on a unique mouse model that carries a rare inherited form of Parkinson’s. Despite its genetic origin, the condition closely resembles the late-onset form that makes up roughly 90 percent of cases.

“This mouse model provides some of the most compelling evidence to date for how mitochondrial dysfunction can cause typical late-onset Parkinson’s disease,” said Dr. Ken Nakamura, who led the study.

“I hope that ultimately, understanding this link will point to new drug targets to prevent or treat all forms of the disease.”

The mouse carries a mutation in a mitochondrial protein called CHCHD2, which is known to cause an inherited version of Parkinson’s.

Because this inherited form closely mirrors the sporadic form that appears without a clear family history, the team believes their findings are relevant to many people with the disease.

Watching the disease unfold

Parkinson’s is not a single, simple condition. The most common sporadic form has many subtypes, shaped by different genes and environmental factors. That mix has made it hard to build animal models that truly match what happens in people.

Dr. Nakamura, who works at the Gladstone Institute of Neurological Disease, pointed out that mice with some mitochondrial mutations linked to Parkinson’s in humans often fail to show the key features of the usual sporadic disease.

Using their new CHCHD2 mouse model, the scientists traced a chain of events inside vulnerable brain cells.

Dr. Kohei Kano is a postdoctoral fellow in Nakamura’s lab and co-first author of the study.

“We were able to watch, step by step, how mitochondria start to fail and how this process eventually leads to the accumulation of alpha-synuclein – the protein that builds up in pathological alterations in the brain called Lewy bodies in nearly all Parkinson’s patients,” said Dr. Kano.

In these mice, the mutated CHCHD2 protein builds up inside mitochondria, which then become swollen and distorted. As damage grows, cells stop using their usual energy pathways and switch to less-efficient ways of burning sugar.

When oxidative stress piles up

As mitochondrial metabolism shifts, the team saw a rise in oxidative stress. Inside cells, unstable molecules called reactive oxygen species started to build up.

Under healthy conditions, other proteins clear out these reactive molecules before they cause trouble. In the CHCHD2 mice, the mutation interferes with that cleanup system, so the harmful molecules accumulate.

Dr. Szu-Chi Liao, co-first author of the study, said a notable finding was that alpha-synuclein doesn’t accumulate until after levels of reactive oxygen species rise. “This order of events is consistent with our hypothesis that oxidative stress is causing the alpha-synuclein to aggregate.”

The timing matters because it links rising oxidative stress to the later clumping of alpha-synuclein, which forms Lewy bodies, a hallmark feature seen in nearly all Parkinson’s patients.

Clues from human brain tissue

To see if the same pattern shows up in people, Dr. Nakamura collaborated with a team of experts at the University of Sydney led by Dr. Glenda Halliday.

The researchers studied post-mortem brain tissue from people with sporadic Parkinson’s. They focused on dopamine-producing neurons that are especially vulnerable in the disease.

In these cells, the experts found that the CHCHD2 mitochondrial protein accumulated in early-stage alpha-synuclein aggregates.

“This work is a blueprint for how a mitochondrial protein can be disrupted and actually cause Parkinson’s disease,” said Dr. Nakamura.

He noted that other triggers could set off the same sequence: mitochondrial damage, energy problems, and buildup of reactive oxygen species – followed by abnormal accumulation of different proteins inside neurons.

That shared cascade could help explain why very different risk factors sometimes lead to similar pathology in the brain.

Next steps in understanding Parkinson’s

The scientists plan to keep digging into how CHCHD2 affects oxidative stress and whether it plays a part in sporadic Parkinson’s.

The experts also want to see if medicines that limit reactive oxygen species and support cellular energy can break the chain of events they saw in both the mouse model and human tissue.

If that idea holds up, it could move research toward treatments that protect mitochondria earlier in the disease.

A clearer picture of these steps may help guide the search for therapies that keep energy levels steady in vulnerable neurons, cut down on oxidative damage, and slow the buildup of harmful protein clusters in Parkinson’s disease.

The full study was published in the journal Science Advances.

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